Phenothiazines

ABSTRACT

BENZOLYALKYLAMINOALKYLPHENOTHIAZINE DERIVATIVES OF THERAPEUTIC INTEREST, COMPOSITIONS CONTAINING SUCH DERIVATIVES, AND METHOD OF TREATING WITH SUCH COMPOSITIONS, ARE DISCLOSED. THESE COMPOUNDS HAVE PARA-SYMPATHOLYTIC, SYMPATHOMIMETIC AND SEDATIVE ACTIVITY USEFUL IN THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS, ESPECIALLY ENDOGENIC DEPRESSIONS.

United States Patent Office 3,833,567 Patented Sept. 3, 1974 ABSTRACT OFTHE DISCLOSURE Ben zoylalkylaminoalkylphenothiazine derivatives oftherapeutic interest, compositions containing such derivatives, andmethod of treating with such compositions, are disclosed. Thesecompounds have para-sympatholyt-ic, sympathomimetic and sedativeactivity useful in the treatment of central nervous system disorders,especially endogenic depressions.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of copending application U.S. Ser. No. 719,665,filed on Apr. 8, 1968, now U.S. Pat. No. 3,637,660.

SUMMARY OF THE INVENTION The present invention concerns a group of newheterocyclic aminoketones having valuable pharmacological properties,compositions thereof, and method of treating therewith.

The new compounds of the present invention arebenzoylalkylaminoalkylphenothiazine derivatives which correspond to thegeneral formula (I):

n is 1, 2 or 3 (n=1 is preferred);

R represents'a phenyl group, optionally substituted with one to three,alike or different, substituents selected from the group consisting ofF, Cl, OH, or CF as well as an alkyl or an alkoxy group containing 1 to4 carbon atoms, inclusive; or a phenyl group substituted at the3,4-positions with an alkylidenedioxy (containing up to 6 carbon atoms,inclusive) group; and R represents H, 'F, Cl, OCH CF or SO N(OHPharamecutical-ly acceptable acid addition salts of the foregoingcompounds are also contemplated.

It has been found that the compounds of this invention arepharmacologically active, especially with regard to the central nervoussystem. They potentiate ap morphine and have para-sympatholytic andsypathomimetic activity. They also antagonize the effects of reserpine.The compounds of formula (I) have, in addition, a sedative activity. Asthe compounds of the invention also show a surprisingly low toxicity,they may be used therapeutically in disorders related to the centralnervous system, especia'lly in depressions.

' Although formula (I) comprises compounds of a relativity wide spectrumof pharmacological properties, which vary-depending on the position andnature of the individual substituents, it seems to be a common characterof them that they are all active on the central nervous system andexhibit a remarkably low toxicity.

This low toxicity is of particular importance considering the highoccurrence of suicides committed with antidepressive agents.

A particularly preferred and advantageous compound is Nmethyl-N(4-chl0r0bertz0yhnethyl)-3-(phenothiazin 10-yl)-propylamine. Theprovision of such novel and valuable compounds, compositions thereof,and a method of treating therewith are among the objects of the presentinvention. Additional objects will become apparent hereinafter and stillother objects will be recognized by one skilled in the art.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The compounds of thegeneral formula (I) can be considered to be built up from the followingfour components, namely N Ra HO (CH2)nC 0 R (II) (III) (IV) the symbolsR R R and n as usd in these formulas and in the following descriptionbeing defined as above, and can be produced by a series of reactions inwhich the amines (III) and (IV) are treated with reactive esters of thealcohols (III) and (V). The order between the components of the moleculeis determined by the structure of the compounds as shown in the generalformula (I). The bonds between the components can, however, beestablished in optional order, as indicated below.

From a general point of view, the compounds can therefore be prepared byreacting the amines of the formulas (II) and (IV) stepwise with reactiveesters of the alcohols of the formulas (III) and (V), the steps beingchosen so that the components will be condensed to form successively thecompound of the formula (I), which may, if desired, be transferred intoa pharmaceutically acceptable addition salt. The reaction may be carriedout in an inert solvent, and the amine of .the formula (II) may be usedin the form of a salt of an alkali metal, preferably lithium or sodium.

The carbonyl group of the alcohol HO(CH )nCOR or of any intermediatederived therefrom, is preferably or, when required, reversiblyprotected, in a manner known per se, preferably as a ketal of a monoordifunctional alcohol.

According to a first embodiment of this process an amine with thegeneral formula (II),

is treated with a reactive ester of an alcohol of the general formulaHOCH2CHCH2N(CH2)11COR3 R1 on,

+ HOCHAIZHCHzOH CHaNH in the presence of an acid binding agent such assodium amide. The reaction is preferably carried out in an inert organicsolvent, such as benzene, toluene, xylene, or dioxane, by heating at atemperature between 50 C. and the boiling point of the reaction mixture.

As reactive esters of the alcohol of the general formula (VI)particularly the esters of hydrohalogenic acids (HCl, HBr or HI) andaromatic or aliphatic sulphonic acids come into consideration.

In a second variation of the general process a secondary amine of thegeneral formula \N/ Rs (311. 311 CH NH R H; (V II) is treated with areactive ester of the alcohol of the general formula HO (CH ),,COR (V)wherein R and n are defined as above. As reactive esters of the alcohol(V) those of hydrochloric and hydrobromic acids are particularlysuitable. The reaction is carried out in the presence of an acid bindingagent, such as a hydroxide, carbonate or hydrogencarbonate of an alkalior alkaline earth metal, or in the presence of an excess of thesecondary amine of formula (VII). The reaction can be carried out invarious solvents, such as hydrocarbons, esters, ketones, or in mixturesof such a solvent with water, at a temperature from C. to the boilingpoint of the reaction mixture.

According to a third embodiment of the process compounds of the generalformula (I) can be obtained by treating an aminoketone of the generalformula,

CH (VIII) with a reactive ester of an alcohol of the general formula R(I X) such as esters of hydrohalogenic acids or of aromatic or aliphaticsulphonic acids as commonly used in the art.

Thereaction is preferably carried out in a solvent medium at atemperature from about 50 C. to the boiling point of the reactionmixture, with or without an acid binding agent, such as an alkalihydroxide, amide, carbonate or hydrogencarbonate. Instead of an acidbinding agent an excess of the amine component may be used in theprocess.

For therapeutic purposes the bases of the general formula (I) may beemployed as such or in the form of acid addition salts containing anionswhich are pharmaceutically acceptable, such as hydrochlorides,hydrobromides, phosphates, nitrates, sulphates, hydrogenoxalates,oxalates, succinates, tartrates, methanesulphonates ethanedisulfonatesso that the beneficial physiological properties are not vitiated byside-effects ascribable to the anions. For some purposes they may beused in the form of quaternary ammonium salts obtained by reaction withorganic halides or other reactive organic esters (e.g. methyl or ethyliodide, chloride, or bromide, or alkyl or benzyl chloride or bromide,methyl or ethyl sulphate or benzensulphonate) The following examples areintended to illustrate the present invention but not to limit the scopethereof.

EXAMPLE 15.2 Parts of 3-methylaminopropanol are dissolved in 50 parts ofbenzene and 11.3 parts of w-chloroacetophenone are added, followed by asolution of 5.2 parts of potassium hydroxide in 50 partsof water. Afterrefluxing for four hours, the reaction mixture isv cooled to roomtemperature and the aqueous phase is discarded. The benzene solution isevaporated todryness'in v' acuo..'l he residue contains Nmethyl-N-benzoylmethylfi-aminopropanol-l. It can be purified bycrystallization as the hydrogen oxalate. M.p. 162 C. (from butanone).

17.3 Parts of N-methyl-N-benzoylmethyl-3-aminoproe panol-I are dissolvedin 50 parts by volume of dry chloroform. A solution of 10.9 parts ofthionyl choride'in 50 parts by volume of dry chloroform isfadded duringa time period of one hour, while stirring, at room temperature. Thesolution is then refluxed for three hours and evaporated to dryness invacuo. The residue is "dissolved in ethanol. Upon careful adding of,ether and cooling the hydrochloride ofN-methyl-N-(3-chloropropyl)-benzoyl methyl-amine separates and isfiltered otf. M.p. 139 140C.

11.7 Parts of 2-chlorophenothiazine are dissolved in 10 parts of drytoluene and 3.1 parts of sodium amide are added and the mixture isrefluxed and stirred for four hours. A solution of 13.5 parts ofN-methyl-N-(3-chloropropyl)-benzoylmethyl-amine in 20 parts of drytoluene is added dropwise and the mixture is stirred and refluxed foreight hours. Y I 7 After cooling to room temperature, water is carefullyadded to the reaction mixture and thetoluene solution is extracted withwater to whichhydrochlorica cid is added so that. the aqueous phaseobtains the pH-value of 5. The aqueous extract is discarded and the.toluene phase is evaporated to. dryness in vacuo. The residue isdissolved in 30 parts of methanol and a solution of 1.8 parts ofhydrogen chloride in 60 parts of butanone is added. After coolingN-methyl-N-benzoylmethylfia(2- chlorophenothiazin-lO-yl)-propylamine'hydrogen chloride crystallizes and is filtered off. M.p. 182-483 C..

EXAMPLE 2 19.5 Parts of 2-bromomethyl-Z-phenyl-l,3-dioxolane are addedto a solution of 56 parts of methylamine in parts of methanol and heatedin an autoclave to C. for 16 hours. After cooling the reaction mixtureis poured into water .and extracted with ether. The ethereal extract isdried, evaporated to dryness and the residue is dissolved in ethanol.Hydrogen chloride is introduced. The hydrochloride ofZ-methyIaminOmethyI-Z} phenyl-1,3-dioxolane separates'as a'crystallineprecipitate and is filtered 01f. M.p. 230 C. I

2.5 Parts of 2-methylaminomethylQ-phenyl-1,3-dioxolane are dissolvedin25 parts of acetonitrileand 3.8 parts of 2-chloro-10-(3-chloropropyl)phenothiazine areadded and the reaction mixture is refluxed for' fourhours. After cooling to room temperature 1.35 parts of hydrogen chloridein 10 parts of water are added The solution is left at room temperaturefor 16 hours and then poured into a solution of 10 partsof potassiumcarbonate in water. The resulting mixture is extracted with-ether. Theethereal extract is evaporated to dryness in vacuo. The residue isdissolved in butanone and a solution of-oxalie acid in butanone isadded. After cooling crystals of the hydrogen oxalate ofN-methyl-N-benzoylmethyl-3-(2% chlorophenothiazin-10 yl)-propylamine(M.p. 182-'183 C.) are obtained. I Y I' EXAMPLE 3 10.5 Parts of2,N-dimethyl 3 (2-methoxyphenothi azine-lO-yl)-propyl-amine and 6.2parts of .w-GhlOrOflCGtO: phenone are dissolved in 60 parts of-benzeneand-a solution of 3.8 parts of potassium hydroxide in:l5 parts of wateris added. The reaction mixturefis refluxed forithreeN-methyl-N-(4-ethoxybenzoylmethyl)-2-methyl-3-(2-methoxyphenothiazin-lO-yl)-propylamine hydrochloride. M.p. 213-215 C.

N-rnethyl-(4-n-butoxybenzoylmethyl)-2-methyl-3-(2-methoxyphenothiazin-10-yl)-propylamine hydrogen oxalate. M.p. 162164 C.

2,N-dimethyl-N- 3 ,4-dimethoxybenzoylmethyl) -3 2-methoxyphenothiazin-l-yl)-propylamine hydrogen oxalate. M.p. 1'60-162 C.

2,N-dimethyl-N- 3 ,4,S-trimethoxy-benzoylmethyl -3- 2-methoxyphenothiazin--yl)-propylamine hydrogen oxalate. M.p. 180182 C.

N-methyl -N- 4-methoxybenzoylmethyl) -3- (2-chlorov phenothiazin-l 0-yl)-propylamine hydrochloride.

M.p. 174-175.5 C. N-rnethyl-N- (4-chlorobenzoylmethyl) -3-(2-chlorophenothiazin-lO-yl)-propylamine hydrochloride.

M.p. 182183 C.

2,N-dimethyl-N- (4-isopropoxyb enzoylmethyl) -3 2-methoxyphenothiazin-10-yl)-propylamine hydrochloride. M.p. 193-.-195 C.

N-methyl-N- 4-chlorobenzoy1methyl) -3-(Z-rnethoxyphenothiazin-10-yl)-propylarnine hydrogen oxalate.

M.p. 159-160 C.

N-methyl-N- (4-methoxybenzoylrnethyl) -3 (2-methoxyphenothiazin-lO-yl)-propylamine hydrogen oxalate.

' M.p. 167-169 C.

N-methyl-N-(4-chlorobenzoylmethyl)-3-(phenothiazin- 1'O-yl)-p'ropylaminehydrogen oxalate.

N-rnethyl-N-(4-methoxybenzoylmethyl)-3-(phenothiazin- 10,-yl)-propylamine hydrogen oxalate. M.p.

N-methyl-N- (4-methoxyb enzoylmethyl) -3-(2-trifluoromethylphenothiazin-l0-yl)-propylamine hydrogen oxalate. M.p.185187 C.

2,N-dimethyl-N- 4-chlorobenzoylmethyl) -3(2-methoxyphenothiazin-lO-yl)-propylamine hydrogen oxalate. M.p. 135 C.

2,'N-dimethyl-N-( 3 ,4-methylendioxybenzoylmethyl) -3-(2-methoxyphenothiazin-10-yl)-propylamine hydrogen oxalate. M.p. 159-160C.

N-methyl-N- 3 ,4-methylendioxybenzoylmethyl) -3 (2-trifiuoro-methylphenothiazin-10-yl) -propylamine hydrogen oxalate. M.p.183 C.

N-methyl-N-(3,4-methylendioxybenzoylmethyl)-3-phenothiazin-10-yl)-propylamine hydrogen oxalate.

- M.p. 172-175 C.

N-methyl-N-(3,4-methylendioxybenzoylmethyl)-3-(2-methoxyphenothiazin-10-yl)-propylamine hydrogen oxalate. M.p. 148149 C.

2,N-dimethyl-N- 3 ,4-ethylene dioxybenzoylmethyl) -3- 2-methoxyphenothiazin- 10-yl)-propylamine hydrochloride. M.p. 17818 C.(decomp.).

EXAMPLE 4 I 16.3 Parts of N -methyl-3-(2-chlorophenothiazin-10-yl)-propylamirie are dissolved in 140 parts of dry acetone, and 16.7 partsof calcium carbonate are added. The mixture is cooled in ice and whilestirring a solution of 28.4 parts'of 2-chl0ropropiophenone is addeddropwise during one hour." The stirring is then continued for four hoursat room temperature. 5.5 Parts of acetic anhydride are then added andthe reaction mixture is left overnight at room temperature. The reactionmixture is then filtered. The residue is extracted with 50 parts of warmmethanol 6 and the extract is combined with the filtrate. Then 200 partsof water are added and potassium carbonate to pH=9. The mixture isextracted with ether. The extract is dired and evaporated to dryness invacuo. The residue is then dissolved in methanol and solution ofhydrogen chloride in ether is added. After cooling N-methyl-N-(2-benzoylethyl) 3 (Z-chlorophenothiazin-10-yl)-propylaminehydrochloride crystallizes and is filtered off. M.p. 154-156 C.

EXAMPLE 5 15.3 Parts of N-methyl 3 (phenothiazin-10-yl)-propylamine aredissolved in 140 parts of dry toluene. 12.2 parts of4-ch1orobutyrophenone and 0.28 parts of potassium iodide are added. Thereaction mixture is refluxed for 16 hours and after cooling extractedwith water. The

EXAMPLE 6 11.5 Parts of N-methyl 3 (2 trifiuoromethylphenothiazin 10yl)-propylamine and 7.1 parts of 4-chlorophenacylbromide dissolved inparts of benzene and a solution of 3 parts of sodium-hydrogencarbonatein 30 parts of water are added. The reaction mixture is stirred forthree hours at room temperature. The aqueous phase is separated anddiscarded. The organic phase is extracted with an aqueous solution ofhydrochloric acid until pH=3.2 was obtained. The organic phase is thendried over anhydrous sodium sulphate, and poured into a solution of anequimolar amount of oxalic acid in butanone. The hydrogen oxalate ofN-methyl-N-(4-chlorobenzoylmethyl) 3 (2trifiuoromethylphenothiazin-10-yl) propylamine crystallizes and isfiltered otf. M.p. 189-191 C."

In the same manner as in the Example above the following compounds areprepared:

N-methyl-N-( 4 hydroxybenoxylmethyl)-3-(phenothiazin--10-yl)-propuylamine from N methyl 3 (phenothiazin- 10-yl)-propylami.neand w-ChlOIO 4 hydroxyacetophenone.

N-methyl-N- (3-ethylbenzoylmethyl) 3 (2-chlorophenothiazin-lO-yl)-propylamine fromN-methyl-3-(2-chlorophenothiazin-lO-yl)-propylamine andw-chloro-3-ethylacetophenone. I

N-methyl N [3,4-(2-butyliden)-dioxybenzoylmethyl]-3-(2-tri.fluoromethylphenothiazin 10 yl)-propylamine from N-methyl 3(2-trifiuoromethylphenothiazin-10- yl)-propylamine and10-chloro-3,4-(2-butyliden)-dioxyacetophenone.

N-methyl-N-(3 fluorobenzoylmethyl) 3 (Z-dimethylsulphamoylphenothiazin10 yl)-propylamine from N-methyl 3 (2-dimethylsulphamolyphenothiazin-10-yl)-propylamine and w-ChlOl'O 3 fluoroacetophenone.

N-methyl-N-(4 trifiuoromethylbenzoylrnethyl) 3 (2- methoxyphenothiazin--10 yl)-propylamine from N-' methyl 3 (Z-methoxyphenothiazin 10yl)-pr0py1- amine and w-bromo-4-trifluoromethylacetophenone.

N-methyl-N-(4 chloro-benzoylmethyl) 3 a (2 fluoro phenothiazin 10yl)-propylamine trom N-methyI 3- (2 fiuorophenothiazin 10fyl)-propylamine and wbromo-4-chloroacetophenone.j I

l The following examples of compositions containing the compounds ofthis inventionare given by way of illus trationronly and are not to beconstrued as limiting.

7 EXAMPLE 7 10,000 tablets of 50 mq. each G. N-methyl-N-(4chlorobenzoylmethyl) 3 phenothiazin-lO-yl)-propylarnine hydrochloride500 Lactose 1600 Starch 560 Polyvinylpyrrolidone 25 Magnesiumstearate 15T alc 150 Water, q.s.

The N-methyl-N-(4 chlorobenzoylmethyl) 3 phenothiazin 10 yl)-propylaminehydrochloride, lactose and starch are mixed together and screened. Thepolyvinyl pyrrolidone is dissolved in a suitable amount of water andadded to said mixture, which is then granulated. The granulated obtainedis then dried and mixed with the magnesiumstearate and the tale,whereafter tablets are made.

EXAMPLE 8 Aqueous suspension for injection Mg. 2,N-dimethyl Nbenzoylmethyl 3 (Z-methoxyphenothiazin-l-yl)propylamine hydrochloride250 Methylcellulose 15 Polyoxyethylenesorbitan, monostearate (Tween 20Distilled water to make 5 ml.

1 Trademark of Atlas Powder Company.

Where the foregoing Examples produce a compound having a methyl or otherlower-alkyl group, it is to be understood that compounds containingother lower-alkyl groups of straight or branched nature and containingup to four carbon atoms inclusive, such as methyl, ethyl, propyl,isopropyl, butyl, sec.-butyl, or t.-butyl are prepared in the samemanner by substitution in the process of the appropriate differentloWer-alkyl starting material. Similarly, where methoxy or otherlower-alkoxy group is present, compounds having other lower-alkoxygroups containing various lower-alkyl groups having up to four carbonatoms inclusive are prepared in the same manner from the appropriatedifferent lower-alkoxy starting material. In the same manner, ortho andmeta substituted products are produced instead of para by utilizing theselected ortho or meta substituted starting material, and vice versa.Similarly, other molecular changes within the scope of the invention arereadily made.

The compounds of the invention are generally characterized by thepharmacological activity hereinbefore stated, making them useful incounteracting certain physiological abnormalities in a living animalbody. Elfective quantities of the pharmacologically active compounds ofthe invention may be administered to a living animal body in any one ofvarious Ways or modes, for example, orally as in capsules or tablets, orparentially in the form of sterile solutions, suspensions, or by pelletimplantation, and in some cases intravenously in the form of sterilesolutions. Other modes of administration are cutaneously,subcutaneously, bucally, intramuscularly, and intraperitoneally.

\As representative of living animal bodies which may be treated with thecompounds and compositions of the invention, and according to the methodof treating of the invention, for alleviation of the same and/or similarconditions as those described, in addition to human beings may bementioned the following. domestic animals such as dogs and cats, farmanimals such as horses, cows, sheep, and goats, fur-bearing animals suchas mink, seal, muskrat, fox, raccoon, ermine, and weasel, and 200animals such as bears, antelope, monkeys, baboons, and the like.

Pharmaceutical formulations are usually prepared from a predeterminedquantity of one or more of the compounds of the invention, preferably insolid form. Such formulations may take the form of powders, elixirs,solutions, pills, capsules, pellets or tablets, with or without, but

preferably with, any one of a large variety of phatmaceuticallyacceptable vehicles or carriers. When adf mixture with a pharmaceuticalvehicle or carrier, theactive ingredient usually comprises from about0.01 to about 75 percent, normally from about 0.05 to about percent, byweight of the composition. Carriers such as starch, sugar, talc,commonly used synthetic and natural gums, water, and the like, may beused in suchformulations. Binders such as gelatin, and lubricants suchas sodium stearate, may be used to form tablets. D-isintegra ting agentssuch as sodium bicarbonate may also be included intablets.

tAlthough relatively small quantities of the activefmaterials of theinvention, even as low as Lo'milligr'a'm,

' may be used in cases of administration to subjctshav:

ing a relatively low body weight, unit dosages are pref erably fivemilligrams or above and preferably twentyfive, fifty, or one-hundredmilligrams, or even higher, depending of course upon the subject treatedand theparticular result desired, as will be apparent to one skilled inthe art. Broader ranges appear to be 0.1 to 500 milligrams per unitdose. The active agents of the invention may be combined foradministration with other pharmacologically active agents, such asanalgesics, tranquilizers, steroids or hormones, or the like, or withbufiers, antacids or the like, and the proportion of the active agent,'.or agents in the compositions may be varied widelyhItflis onlynecessary that the active ingredientof the invention constitute aneffective amount, i.e., such that a suitable effective dosage will beobtained consistent with the dosage form employed. Obviously, severalunit dosage forms may be administered at about the same t'ime. The exactindividual dosages as Well as daily dosages in a particular case will ofcourse be determined according to well-established medical and/orveterinary principles.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made inthe com pounds, compositions and methods ofthe present invention without departing from the spirit or scopethereof.

What is claimed is:

1. A compound selected from the group consisting of (A)N-(benzoylalkylaminoalkyl)-phenothiazine derivatives of the formula s:@iN Ra wherein R is selected from the group consisting of H and CH n isselected from the group consisting of 1, 2 and 3; R is selected from thegroup consisting ofa phenyl group optionally substituted with not morethan three, alike or different, substituents selected from the groupconsisting of F, Cl, 0H, CF as Well as an alkyl and an alkoxy groupcontaining not more than 4 carbon atoms or a phenylv group substitutedat 3,4-positions with an alkylidene dioxy group having one ortwo carbonatoms in the alkylidene moiety; R is selected from the group consistingof H, F, Cl, OCHg, O1 and (B) pharmaceutically acceptable acid additionsalts thereof. p v l 2. A compound of Claim 1, which is selectedfror'n'the group consisting of N-methyl-N-(4-chloi'obenzoylmethyl)B-(phenothiazin-lO-yl)-propyla.mine and its" pharmaceuti callyacceptable acid addition salt. 3. A compound of Claim 1, which isselected from the group consisting of N-benzoylmethyl-2,N dimethyl-3 (2%maceutically acceptable acid additi'ori'salt;

4. A compound of Claim 1, which is selected from the group consisting ofN-methyl-N- (4-chlor0benzoylmethyl)- 3 (2trifiuoromethylphenothiazin-10-yl)-propylamine and its pharmaceuticallyacceptable acid addition salt.

5. A compound of Claim 1, which is selected from the group consisting ofN-methyl-N-(4-chlorobenzoylmethyl)- 3 (2chlorophenothiazin-lO-yl)-propylamine and its pharmaceuticallyacceptable acid addition salt.

6. A compound of Claim 1, which is selected from the group consisting ofN-methyl-N- (4-chlorobenzoy1methyl)- 3 (2methoxyphenothiazin-lO-yl)-propylamine and its pharmaceuticallyacceptable acid addition salt.

References Cited UNITED STATES PATENTS 3,058,979 10/1962 Ullyot 2602433,000,886 9/1961 Edgerton et a1. 260243 2,890,219 6/1959 Cusic 260-243HARRY I. MOATZ, Primary Examiner US. Cl. X.R.

